Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C‐MYC depletion

The down‐regulation of dominant oncogenes, including C‐MYC, in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified. In the current study, we demonstrate that MYC‐depleted melanoma cells undergo extensive DNA damage that is caused by the underexpression of thymidylate synthase (TS) and ribonucleotide reductase (RR) and subsequent depletion of deoxyribonucleoside triphosphate pools. Simultaneous genetic inhibition of TS and RR in melanoma cells induced DNA damage and senescence phenotypes very similar to the ones caused by MYC‐depletion. Reciprocally, overexpression of TS and RR in melanoma cells or addition of deoxyribonucleosides to culture media substantially inhibited DNA damage and senescence‐associated phenotypes caused by C‐MYC depletion. Our data demonstrate the essential role of TS and RR in C‐MYC‐dependent suppression of senescence in melanoma cells.Keywords: ribonucleotide reductase, oncogene‐induced senescence, dNTP, myc, melanoma, thymidylate synthas

Induction and transmission of oncogene-induced senescence

Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we discuss emerging concepts in senescence transmission and heterogeneity in primary and secondary senescence on a cellular and organ level

Lipid Motif of a Bacterial Antigen Mediates Immune Responses via TLR2 Signaling

The cross-talk between the innate and the adaptive immune system is facilitated by the initial interaction of antigen with dendritic cells. As DCs express a large array of TLRs, evidence has accumulated that engagement of these molecules contributes to the activation of adaptive immunity. We have evaluated the immunostimulatory role of the highly-conserved outer membrane lipoprotein P6 from non-typeable Haemophilus influenzae (NTHI) to determine whether the presence of the lipid motif plays a critical role on its immunogenicity. We undertook a systematic analysis of the role that the lipid motif plays in the activation of DCs and the subsequent stimulation of antigen-specific T and B cells. To facilitate our studies, recombinant P6 protein that lacked the lipid motif was generated. Mice immunized with non-lipidated rP6 were unable to elicit high titers of anti-P6 Ig. Expression of the lipid motif on P6 was also required for proliferation and cytokine secretion by antigen-specific T cells. Upregulation of T cell costimulatory molecules was abrogated in DCs exposed to non-lipidated rP6 and in TLR2−/− DCs exposed to native P6, thereby resulting in diminished adaptive immune responses. Absence of either the lipid motif on the antigen or TLR2 expression resulted in diminished cytokine production from stimulated DCs. Collectively; our data suggest that the lipid motif of the lipoprotein antigen is essential for triggering TLR2 signaling and effective stimulation of APCs. Our studies establish the pivotal role of a bacterial lipid motif on activating both innate and adaptive immune responses to an otherwise poorly immunogenic protein antigen

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

Slowing down the Grand Touring Prototype speed of cancer cells

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New evidence from Italy (Adamello Group, Lombardy) for analysing the ongoing decline of Alpine glaciers

Glaciers worldwide are showing overwhelming evidence of the impact of climatic change. In the Alpine region the warming experienced since the early 1980s, while synchronous with warming at the global scale, is of a far greater amplitude and exceeds 1 \ub0C, which represents roughly a three-fold amplification of the global climate signal. To evaluate the magnitude of climate change impacts, recent data covering large and representative areas are needed. This paper is aimed at contributing to describe the recent evolution of Alpine glaciers by analysing surface area changes in a representative subset of data (34 glaciers located in the Adamello Group, Lombardy, Italy). Four surface area records, for the years 1983, 1991, 1999 and 2003, were analysed. The 1983, 1999 and 2003 surface area records were compiled by the authors by combining aerial photo analysis, Differential Global Positioning System (DGPS) surveys of glaciers and Geographic Information System (GIS) data processing. The analysis led to a quantification of surface reduction: c. 19% from 1983 to 2003 for glaciers in the Adamello group. Small glaciers proved to contribute strongly to total area loss: in 2003, 31 glaciers (c. 91% of the total number) were smaller than 1 km2, covering 2.28 km2 (c. 10% of the total area), but accounted for 39% of the total loss in area (losing 2.05 km2 from 1983 to 2003). The rate of area change accelerated in the later period, with surface reduction between 1999 and 2003 amounting to c. 5.5% (with respect to the 1999 total glacier coverage), equal to a mean area loss of c. 0.34 km 2 /year; the mean yearly loss over the previous period (1991-1999) was found equal to 0.23 km2/year. This acceleration coincided with a clear local warming and a small local decrease in snow cover depth and duration which resulted strongly related to North Atlantic Oscillation (NAO) winter variability

Future hydrological regimes in the upper Indus basin : a case study from a high-altitude glacierized catchment

The mountain regions of the Hindu Kush, Karakoram, and Himalayas (HKH) are considered Earth's "third pole," and water from there plays an essential role for downstream populations. The dynamics of glaciers in Karakoram are complex, and in recent decades the area has experienced unchanged ice cover, despite rapid decline elsewhere in the world (the Karakoram anomaly). Assessment of future water resources and hydrological variability under climate change in this area is greatly needed, but the hydrology of these high-altitude catchments is still poorly studied and little understood. This study focuses on a particular watershed, the Shigar River with the control section at Shigar (about 7000km2), nested within the upper Indus basin and fed by seasonal melt from two major glaciers (Baltoro and Biafo). Hydrological, meteorological, and glaciological data gathered during 3 years of field campaigns (2011-13) are used to set up a hydrological model, providing a depiction of instream flows, snowmelt, and ice cover thickness. The model is used to assess changes of the hydrological cycle until 2100, via climate projections provided by three state-of-the-art global climate models used in the recent IPCC Fifth Assessment Report under the representative concentration pathway (RCP) emission scenarios RCP2.6, RCP4.5, and RCP8.5. Under all RCPs, future flows are predicted to increase until midcentury and then to decrease, but remaining mostly higher than control run values. Snowmelt is projected to occur earlier, while the ice melt component is expected to increase, with ice thinning considerably and even disappearing below 4000m MSL until 2100